ANALOGS OF PEPTIDE YY AND USES THEREOF

Abstract: The invention provides analogs of PYY. The invention also provides compositions and methods useful for controlling biological activities such as cell proliferation, nutrient transport, lipolysis, and intestinal water and electrolyte secretion.

Description: ANALOGS OF PEPTIDE YY AND USES THEREOF Statement as To Federally Sponsored Research This invention was made in part with Government funding and the Government therefore has certain rights in the invention. Background of the Invention This invention relates to peptide derivatives which are useful as therapeutic agents in the treatment of gastroenterological disorders. Peptide YY (PYY) is a 36-residue peptide amide isolated originally from porcine intestine, and localized in the endocrine cells of the gastrointestinal tract and pancreas (Tatemoto et al. Proc. Natl . Acad. Sci . 79:2514, 1982) . Peptide YY has N-terminal and C-terminal tyrosine amides; accordingly, these two tyrosines give PYY its name (Y represents the a ino acid tyrosine in the peptide nomenclature) . In addition PYY shares a number of central and peripheral regulatory roles with its homologous peptide neuropeptide Y (NPY) , which was originally isolated from porcine brain (Tatemoto, Proc . Natl . Acad . Sci . 79:5485, 1982). In contrast with the cellular location of PYY, NPY is present in submucous and myenteric neurons which innervate the mucosal and smooth muscle layers, respectively (Ekblad et al. Neuroscience 20:169, 1987). Both PYY and NPY are believed to inhibit gut motility and blood flow (Laburthe, Trends Endocrinol . Metab . 1:168, 1990), and they are also thought to attenuate basal (Cox et al. Br. J. Pharmacol . 101:247, 1990; Cox et al. J. Physiol . 398:65, 1988; Cox et al. Peptides 12:323, 1991; Friel et al. Br. J. Pharmacol . 88:425, 1986) and secretagogue-induced intestinal secretion in rats (Lundberg et al. Proc. Natl . Acad . Sci USA 79:4471, 1982; Playford et al. Lancet 335:1555, 1990) and humans (Playford et al. supra) , as well as stimulate net absorption (MacFadyen et al. Neuropeptides 7:219, 1986) . Furthermore, plasma PYY levels have been reported to be elevated in several diseases that cause diarrhea (Adrian et al. Gastroenterology 89:1070, 1985). Taken together, these observations suggest that PYY and-NPY are released into the circulation after a meal (Adrian et al. Gastroenterology 89:1070, 1985; Balasubramaniam et al. Neuropeptides 14:209, 1989), and thus may play a physiological role in regulating intestinal secretion and absorption, serving as natural inhibitors of diarrhea. A high affinity PYY receptor system which exhibits a slightly higher affinity for PYY than NPY has been characterized in rat intestinal epithelia (Laburthe et al. Endocrinology 118:1910, 1986; Laburthe, Trends Endocrinol . Metab. supra) and shown to be negatively coupled to adenylate cyclase (Servin et al. Endocrinology 124:692, 1989). Consistently, PYY exhibited greater antisecretory potency than NPY in voltage clamped preparations of rat small intestine (Cox et al. J. Physiol . supra) , while C-terminal fragments of NPY were found to be less effective in their antisecretory potency than PYY (Cox et al. Br. J. Pharmacol , supra) . Structure-activity studies using several partial sequences have led to the identification of PYY(22-36) as the active site for interacting with intestinal PYY receptors (Balsubramaniam et al. Pept . Res . 1:32, 1988). In addition, PYY has been implicated in a number of physiological activities including nutrient uptake (see, e.g., Bilcheik et al. Digestive Disease Week 506:623, 1993), cell proliferation (see, e.g., Laburthe, Trends Endocrinol . Metab . 1:168, 1990; Voisin et al. J. Biol . Chem, 1993), lipolysis (see, e.g.. Valet et al., J. Clin . Invest . 85:291, 1990), and vasoconstriction (see, e.g., Lundberg et al., Proc. Natl. Acad. SCi., USA 79: 4471, 1982). The amino acid sequences of porcine and human PYY are as follows: porcine PYY YPAKPEAPGEDASPEELSRYYASLRHYLNLVTRQRY (SEQ. -ID. -NO. 1) human PYY YPIKPEAPGEDASPEE NRYYASLRHYLNLVTRQRY (SEQ. ID. NO. 2) The amino acid sequence for dog PYY and rat is the same as porcine PYY. Summary of the Invention In one aspect, the present invention features novel analogs of peptide YY of the formula: R ι R 3 R 2 -X-A 22 -A 23 -A 24 -A 25 -A 26 -A 27 -A 28 -A 29 -A 30 -A 31 -A 3 -Y-R 4 wherein X is a chain of 0-5 amino acids, inclusive, the N- ter inal one of which is bonded to R χ and R 2 ; Y is a chain of 0-4 amino acids, inclusive, the c- terminal one of which is bonded to R 3 and R 4 ; x is H, C^C-*^ alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl, naphthaleneacetyl) , C-^C-^ acyl (e.g., formyl, acetyl, and myristoyl) , 7 " C 18 aralkyl (e.g., benzyl), or C 7 -C 18 alkaryl (e.g., p-methylphenyl); R 2 is H, C-L-C^ alkyl (e.g., methyl), C 6 -C 18 aryl (e.g. , .phenyl,naphthaleneacetyl) , C j -C-*^ acyl (e.g., formyl, acetyl, and myristoyl), C 7 -C 18 aralkyl (e.g. ,benzyl) , or C 7 -C 18 alkaryl (e.g. , p-methylphenyl) ; A 22 is an aromatic amino acid, Ala, Aib, Anb, N-Me-Ala, or is deleted; A 23 is Ser, Thr, Ala, Aib, N-Me-Ser, N-Me-Thr, N Me-Ala, or is deleted; A 24 is Leu, lie, Val, Trp, Gly, Aib, Anb, N-Me-Leu, or is deleted; A 25 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e-NH-R (where R is H, a branched or straight chain C^C-^ alkyl group, or an aryl group) , Orn, or is deleted; A 26 is Ala, His, Thr, 3-Me-His, 1-Me-His, 3-pyrozolylalanine, N-Me-His, Arg, Lys, homo- Arg, diethyl-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C^C-^ alkyl group, or an aryl group) , Orn, or is deleted; A 27 is an aromatic amino acid other than Tyr; A 28 is Leu, lie, Val, Trp, Aib, Anb, or N-Me-Leu; A 29 is Asn, Ala, Gin, Gly, Trp, or N-Me-Asn; A 30 is Leu, lie, Val, Trp, Aib, Anb, or N-Me-Leu; A 31 is Val, He, Trp, Aib, Anb, or N-Me-Val; A 32 is Thr, Ser, N-Me-Ser, N-Me-Thr, or D-Trp; R 3 is H, C^C*-^ alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl, naphthaleneacetyl) , C j -C-^ acyl (e.g., formyl, acetyl, and myristoyl), c 7 " c i 8 aralkyl (e.g., benzyl), or C 7 -C 18 alkaryl (e.g., p-methylphenyl); and R 4 is H, C 1 -C 12 alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl, naphthaleneacetyl), C^C-^ acyl (e.g., formyl, acetyl, and myristoyl), c 7 " c i 8 aralkyl (e.g., benzyl), or C 7 -c 18 alkaryl (e.g., p-methylphenyl), or a pharmaceutically acceptable salt thereof. In preferred embodiments. A 27 is Phe, Nal, Bip, Pep, Tic, Trp, Bth, Thi, or Dip. In preferred embodiments X is A 17 -A 18 -A 19 -A 20 -A 21 wherein A 17 is Cys, Leu, He, Val, Aib, Anb, or N-Me-Leu; A 18 is Cys, Ser, Thr, N-Me-Ser, or N-Me-Thr; A 19 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or C 6 -C 18 aryl group), Cys, or Orn; A 20 is an aromatic amino acid, or Cys; and A 21 is an aromatic amino acid, Cys, or a pharmaceutically acceptable salt thereof. In yet other preferred embodiments, Y is A 33 -A 34 -A 35 -A 36 wherein A 33 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e-NH-R (where R is H, a branched or straight chain c ι~ c ιo alkyl group, or an aryl group) , Cys, or Orn; A 34 is Cys, Gin, Asn, Ala, Gly, N-Me-Gln, Aib, or Anb; A 35 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e-NH-R(where R is H, a branched or straight chain C 1 -c 10 alkyl group, or an aryl group) , Cys, or Orn; and A 36 is an aromatic amino acid, Cys or a pharmaceutically acceptable salt thereof. Preferably, the compound has the formula: N-α-Ac- Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg- Tyr-NH 2 (SEQ. ID. NO. 3), H-Ala-Ser-Leu-Arg-His-Phe-Leu- Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH 2 (SEQ. ID. NO. 4), N- α-Ac-Ala-Ser-Leu-Arg-His-Trp-Leu-Asn-Leu-Val-Thr-Arg-Gln- Arg-Tyr-NH 2 (SEQ. ID. NO. 5) , N-α-Ac-Ala-Ser-Leu-Arg-His- Thi-Leu-Asn-Leu-Vaϊ-Thr-Arg-Gln-Arg-Tyr-NH 2 (SEQ. ID. NO. 6) , N-α-Ac-Tyr-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr- Arg-Gln-Arg-Tyr-NH 2 (SEQ. ID. NO. 7) or a pharmaceutically acceptable salt thereof. In another aspect the invention features novel analogs of peptide YY of the formula: *1 R 3 \ / R 2 -A 25 -A 26 -A 27 -A 28 -A 9 -A 30 -A 31 -A 32 -Y-R 4 wherein the N-terminal amino acid is bonded to R χ and R 2 ; Y is a chain of 0-4 amino acids, inclusive the C-terminal one of which is bonded to R 3 and R 4 ; R-L is H, C 1 -C 12 alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl, napthaleneacetyl) , C 1 -C 12 acyl (e. g. , formyl, acetyl, and myristoyl), C 7 -C 18 aralkyl (e.g., benzyl), or C 7 -C 18 alkaryl (e.g., p-methylphenyl) ; R 2 is H, C j^ -C^ alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl, napthaleneacetyl), C 1 -C 12 acyl (e.g., formyl, acetyl, and myristoyl), C 7 -C 18 aralkyl (e.g., benzyl), or C 7 -C 18 alkaryl (e.g., p-methylphenyl) ; A 25 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e-NH-R (where R is H, a branched or straight chain ι~ c ιo alkyl group, or an aryl group) , Orn, or is deleted; A 26 is Ala, His, Thr, 3-Me-His, 1-Me-His, 3-pyrozolylalanine, N-Me-His, Arg, Lys, homo- Arg, diethyl-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -c 10 alkyl group, or an aryl group) , Orn, or is deleted; A 27 is an aromatic amino acid; A 28 is Leu, He, Val, Trp, Aib, Anb, or N-Me-Leu; A 29 is Asn, Ala, Gin, Gly, Trp, or N-Me-Asn; A 30 is Leu, He, Val, Trp, Aib, Anb, or N-Me-Leu; A 31 is Val, He, Trp, Aib, Anb, or N-Me-Val; A 32 is Thr, Ser, N-Me-Ser, N-Me-Thr, or D-Trp; R 3 is H, C- L -C-^ alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl, napthaleneacetyl), C -C--^ acyl (e.g., formyl, acetyl, and myristoyl), C 7 -c 18 aralkyl (e.g., benzyl), or C 7 -c 18 alkaryl (e.g., p-methylphenyl); and R 4 is H, C- L -C-^ alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl, napthaleneacetyl), C 1 -C 12 acyl (e.g., formyl, acetyl, and myristoyl), C 7 -C 18 aralkyl (e.g., benzyl), or C 7 -C 18 alkaryl (e.g., p-methylphenyl), or a pharmaceutically acceptable salt thereof. In preferred embodiments A 27 is Phe, Nal, Bip, Pep, Tic, Trp, Bth, Thi, or Dip. In preferred embodiments Y is A 33 -A 34 -A 35 -A 36 wherein A 33 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e-NH-R (where R is H, a branched or straight chain c ι~ c ιo alkyl group, or C 6 -C 18 aryl group) , Cys, or Orn; A 34 is Gin, Asn, Ala, Gly, N-Me-Gln, Aib, Cys, or Anb; A 35 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e-NH-R (where R is H, a branched or straight chain c ι~ c ιo alkyl group, or C 6 -C 18 aryl group) , Cys, or Orn; and A 36 is an aromatic amino acid, Cys, or a pharmaceutically acceptable salt thereof. Preferably, the compound has the formula N-α-Ac-Arg-His-Phe-Leu-Asn- Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH 2 (SEQ. ID. NO. 8). In another aspect, the invention features novel dimeric analogs of peptide YY. The dimer may be formed by either including two peptides of Formula I, two peptides of Formula II, or one peptide of Formula I and one peptide of Formula II. In one embodiment, the dimer is formed by utilizing a dicarboxylic acid linker capable of binding to a free amine, either primary or secondary, located within each peptide. See, e.g., R. Vavrek and J. Stewart, Peptides: Structure and Function 381-384 (Pierce Chemical Co. 1983) . Examples of suitable dicarboxylic acid linkers are succinic acid, glutamic acid, and phthalic acid. In other embodiments, the dimer is formed by utilizing an amino acid linker capable of binding to a free amine group of one peptide and a free carboxyl group of the other peptide. Preferably, the amino acid linker is a non α-amino acid. Examples of suitable amino acid linkers are amino-caproic acid and amino-valeric acid. In yet another embodiment, the dimer is formed by a disulfide bridge between cysteines located within each peptide. See, e.g., M. Berngtowicz and G. Piatsueda, Peptides: structure and Function 233-244 (Pierce Chemical Co. 1985); F. Albericio, et al., Peptides 1990. 535 (ESCOM 1991) . The symbol X, Y, Z; A 22 , A 23 , A 24 , and the like; and Ser, Leu or the like, as found in a peptide sequence herein stands for an amino acid residue, i.e., =N-CH(R)-CO- when it is at the N-terminus, or -NH-CH(R)-CO-N= when it is at C-terminus, or -NH-CH(R)- CO- when it is not at the N- or C-terminus, where R denotes the side chain (or identifying group) of an amino acid or its residue. For example, R is -CH 2 COOH for Asp, R is -H for Gly, R is -CH 2 OH for Ser, R is -CH 3 for Ala and R is -CH 2 CH 2 CH 2 CH 2 NH 2 for Arg. Also, when the amino acid residue is optically active, it is the L-form configuration that is intended unless the D-form is expressly designated. As set forth above and for convenience in describing this invention, the conventional and nonconventional abbreviations for the various amino acids are used. They are familiar to those skilled in the art; but for clarity are listed below. All peptide sequences mentioned herein are written according to the usual convention whereby the N-terminal amino acid is on the left and the C-terminal amino acid is on the right. A short line between two amino acid residues indicates a peptide bond. Orn = Ornithine Nal = 2-napthylalanine Thi = 2-thienylalanine Pep = 4-chlorophenylalanine Bth = 3-benzothienyalanine Bip = 4,4 '-biphenylalanine Tic = tetrahydroisoquinoline-3-carboxylic acid Aib = aminoisobutyric acid Anb = α-aminonormalbutyric acid Dip = 2,2-diphenylalanine Thz = 4-Thiazolylalanine The compounds of the present invention can be provided in the form of pharmaceutically acceptable salts. Examples of preferred salts are those with therapeutically acceptable organic acids, e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, salicylic, methanesulfonic, toluenesulfonic, trifluoroacetic, or pamoic acid, as well as polymeric acids such as tannic acid or carboxymethyl cellulose, and salts with inorganic acids, such as hydrohalic acids, e.g., hydrochloric acid, sulfuric acid, or phosphoric acid and the like. In another aspect, the invention features one of the above compounds and a pharmaceutically acceptable carrier substance in a therapeutic composition capable of decreasing excess intestinal water and electrolyte secretion. In preferred embodiments, the composition is in the form of a liquid, pill, tablet, or capsule for oral administration; a liquid capable of being administered nasally as drops or spray or a liquid for intravenous, subcutaneous, parenteral, intraperitoneal or rectal administration. The therapeutic composition can also be in the form of an oil emulsion or dispersion in conjunction with a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained-release composition for subcutaneous or intramuscular administration. For maximum efficacy, zero-order release is desired. In another aspect the invention features, a method for decreasing excess intestinal water and electrolyte secretion in a mammal, the method comprising administering to the mammal, e.g., a human, a therapeutically effective amount of the above mentioned compounds. In addition, the invention features a method of . regulating cell proliferation in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the composition of the above mentioned compounds. Preferably, the method regulates the proliferation of an intestinal cell. The invention also features methods for increasing nutrient transport, regulating lipolysis, and regulating blood flow in a mammal, the methods comprising administering to the mammal a therapeutically effective amount of the above mentioned compositions. The compounds of the invention exhibit a broad range of biological activities related to their antisecretory and antimotility properties. The compounds are believed to suppress gastrointestinal secretions by direct interaction with epithelial cells or, perhaps, by inhibiting secretion of hormones or neurotransmitters which stimulate intestinal secretion. The compounds of the invention may also control intestinal blood flow which in turn may modulate intestinal hydrostatic pressure in favor of net water absorption. The compounds of the invention are especially useful in the treatment of any number of gastrointestinal disorders (see e.g., Harrison 's Principles of Internal Medicine , McGraw-Hill Inc., New York, 12th Ed.) that are associated with excess intestinal electrolyte and water secretion as well as decreased absorption, e.g., infectious (e.g., viral or bacterial) diarrhea, inflammatory diarrhea, short bowel syndrome, or the diarrhea which typically occurs following surgical procedures, e.g. , ileostomy. Examples of infectious diarrhea include, without limitation, acute viral diarrhea, acute bacterial diarrhea (e.g., salmonella, campylobacter, and clostridium or due to protozoal infections), or traveller's diarrhea (e.g., Norwalk virus or rotavirus) . Examples of inflammatory diarrhea include, without limitation, malabsorption syndrome, tropical spue, chronic pancreatitis, Crohn's disease, diarrhea, and irritable bowel syndrome. It has also been discovered that the peptides of the invention can be used to treat an emergency or life-threatening situation involving a gastrointestinal disorder, e.g., after surgery or due to cholera. Furthermore, the compounds of the invention can be used to treat patients suffering from Acquired Immune Deficiency Syndrome (AIDS) , especially during cachexia. The compounds of the invention are also useful for inhibiting small intestinal fluid and electrolyte secretion, augmenting nutrient transport — as well as increasing cell proliferation — in the gastrointestinal tract, regulating lipolysis in, e.g, adipose tissue, and regulating blood flow in a mammal. The compounds of the invention are advantageous because they are truncated versions of the natural PYY peptide; thus, the shorter peptide not only facilitates easier synthesis and purification of the compounds, but also improves and reduces manufacturing procedures and expenses. Moreover, a shorter PYY compound is advantageous because such peptides will interact solely with PYY receptors and not with homologous receptors such as NPY Yl and Y3; thus, minimizing unwanted agonist or antagonist side reactions. Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims. Detailed Description The drawings will first be described. Drawings FIG. 1 shows a semipreparative reversed phase chromatogram of N- -Ac-[Phe 27 ]PYY(22-36) (SEQ. ID. NO. 3) («25mg) obtained by HF cleavage. Conditions: Vydac C18 semipreparative column (250 X 10mm, 300 Λ pore size, 10 micron particle size); flow rate 4.7 ml/min; fractions l, 2, 3, and 4 were collected and analyzed by analytical chromatography. The homogeneous fractions (1-3) were combined and dried in a speed vac. FIG. 2 shows a graph of the inhibition of 125 I- PYY binding to rat jejunal membranes by increasing concentrations of PYY (SEQ. ID. NO. 1), PYY(22-36) (SEQ. ID. NO. 10), [Im-DNP-His 26 ]PYY (SEQ. ID. NO. 9), [Ala 32 ]PYY(22-36) (SEQ. ID. NO. 11), [Ala 23 ' 32 ]PYY(22-36) (SEQ. ID. NO. 12), [Glu 28 ]PYY(22-36) (SEQ. ID. NO. 13), N- α-Ac-PYY(22-36) (SEQ. ID. NO. 14), N-Q-Ac-[p.Cl- Phe 28 ]PYY(22-36) (SEQ. ID. NO. 15), N-α-Ac-[Glu 26 ]PYY(22- 36) (SEQ. ID. NO. 16), N-α-Ac-[Phe 27 ]PYY(22-36) (SEQ. ID. NO. 3), N-α-Ac-[N-Me-Tyr 26 ]PYY(22-36) (SEQ. ID. NO. 17), N- α-Myristoyl-PYY(22-36) (SEQ. ID. NO. 18), N-α- Naphthaleneacetyl-PYY(22-36) (SEQ. ID. NO. 19), and PYY (22-26) (SEQ. ID. NO. 10). FIGS. 3A-B show the antisecretory effects of PYY (SEQ. ID. NO. 1), PYY(22-36) (SEQ. ID. NO. 10) and analogs up one baseline short circuit current (SCC) in voltage clamped preparation of rat jejunum. Values of changes in SCC are quoted of μA/0.6cm 2 , mean ±SEM from between 3 and 7 different jejunal preparations. Peptides shown in A and B are denoted by the same symbol as in FIG. 2. FIG. 4 shows a graph of the inhibition of 125 I-PYY binding to rat jejunal membranes by increasing concentrations of PYY, N-α-Ac-PYY(22-36) (SEQ. ID. NO. 14), N-α-Ac-[Tic 27 ]PYY(22-36) (SEQ. ID. NO. 25), N-α-Ac- [Bip 27 ]PYY(22-36) (SEQ. ID. NO. 22), N-α-Ac-[Nal 27 ]PYY(22- 36) (SEQ. ID. NO. 23), N-α-Ac-[Bth 27 ]PYY(22-36) (SEQ. ID. NO. 21), N-α-Ac-[Phe 27 ]PYY(22-36) (SEQ. ID. NO. 3), N-α-Ac- [Phe 27 ]PYY(25-36) (SEQ. ID. NO. 26), N-α-Ac-[Trp 27 ]PYY(22- 36) (SEQ. ID. NO. 5), and N-α-Ac-[Thi 27 ]PYY(22-36) (SEQ. ID. NO. 6) . There now follows a description of the synthesis, analysis for biological efficacy and use of the preferred embodiments of the invention. In order to determine the structural requirements necessary to elicit antisecretory effects, several analogs of the PYY active site, PYY(22- 36) , were synthesized and their binding and antisecretory potencies in rat jejunum were compared. We now describe the structure, synthesis, and use of preferred embodiments of the invention. STRUCTURE The peptides of the invention have the general formula recited in the Summary of the Invention above. They all have an aromatic amino acid group at position 27 which is important for both antisecretory activity and utility as antidiarrheal compounds. SYNTHESIS The peptides of the present invention may be synthesized by any techniques that are known to those skilled in the peptide art. An excellent summary of the many techniques so available may be found in Solid Phase Peptide Synthesis 2nd ed. (Stewart, J.M. and Young, J. D. Pierce Chemical Company, Rockford, IL, 1984). The peptides listed in Table 1 and Table 2 were synthesized as follows. Peptide synthesis was performed on an Applied Biosystems Model 430A synthesizer. Amino acid and sequence analyses were carried out using Waters Pico-Tag and Applied Biosystems Model 470A instruments, respectively. Peptides were purified using a Waters Model 600 solvent delivery system equipped with a Model 481 Spectrophotometer and U6K injector according to standard protocols. Peptide masses were determined at the University of Michigan, Protein Chemistry Facility, Ann Arbor, Michigan according to standard methods. All Boc-L-amino acid derivatives, solvents, chemicals and the resins were obtained commercially and used without further purification. Paramethylbenzhydroxylamine (MBHA) resin (0.45 mmol, -NH 2 ) was placed in the reaction vessel of the peptide synthesizer and the protected amino acid derivatives were sequentially coupled using the program provided by the manufacturers modified to incorporate a double coupling procedure (see, e.g., Balasubramaniam et al., Peptide Research 1: 32, 1988). All amino acids were coupled using 2.2 equivalents of preformed symmetrical anhydrides. Arg, Gin and Asn, however, were coupled as preformed 1-hydroxybenzotriazole (HOBT) esters to avoid side reactions. At the end of the synthesis, the N-α-Boc group was removed and in some instances the free α-NH2 was acetylated by reaction with acetic anhydride (2 equivalents) and diisopropyl ethylamine until a negative ninhydrin test was obtained (Anal. Biochem. 34:595, 1970). The peptide resin (--1.0 g) was then treated with HF (10 ml) containing p-cresol (-0.8 g) for 1 h at -2 to -4 °C. The HF was evacuated and the residue was transferred to a fritted filter funnel with diethyl ether, washed repeatedly with diethyl ether, extracted with acetic acid (2 X 15 ml) and lyophilized. The crude peptides thus obtained were purified by semipreparative RP-HPLC as shown in Fig. 1. Examples of the synthesized nalogs are: [itn-DNP-His 26 )PYY _. YPAKPEAPGEDASPEELSRYYASLR [im-DNP-His"] YLNLVTRORY-NH 2 (SEQ. ID No. 9) PYYC22-36) A S L R H Y L N L V T R Q R Y-NH 2 (SEQ. ID No. 10) [Ala 32 ] PYY A S L R H Y L N L V [Ala] R Q R Y-NH 2 (SEQ. ID No. 11) [A I a 23 ' 32 ] PYY A [Ala] L R H Y L N L V [Ala] R 0 R Y-NH 2 (SEQ. ID No. 12) [Glu 28 ]PYY(22-36) A S L R H Y [Glu] N L V T R Q R Y-NH 2 (SEQ. ID No. 13) N-α-Ae-PYY(22-36) N-α-Ac-A S L R H Y L N L V T R O R Y-NH 2 (SEQ. ID No. 14) N-α-Ac [p.Cl. Phe 26 ] PYY N-α-Ac-A S L [p.Cl. Phe") Y L N L V T R Q R Y-NH 2 (SEQ. ID No. 15) N-α-Ac[Glu 28 ]PYY N-α-Ac-A S L R H Y [Glu] N L V T R 0 R Y-NH 2 (SEQ. ID No. 16) N-α-Ac [Phe 27 ] PYY N-α-Ac-A S L R H [Phe] E N L V T R O R [N-Me-Tyr] -NH., (SEQ. ID No. 3) N-α-Ac [N-Me-Tyr 36 ] PYY N-α-Ac-A S L R H Y E N L V T R O R [N-Me-Tyr] -NH 2 (SEQ. ID No. 17) N-α-ιnyri8toyl-PYY(22-36) N-α-myristoyl-A S L R H Y L N L V T R Q R Y-NH 2 (SEQ. ID No. 18) N-α-naphthaleneacetyl-PYY(22-36) N-α-πaphthaleneacetyl -A S L R H Y L N L V T R O R Y-NH 2 (SEQ. ID No. 19) N-α-Ac [Phe 27 ] PYY N-α-Ac-A S L R H [Phe] E N L V T R O R [N-Me-Tyr] -NHg (SEQ. ID No. 3) N-α-Ac-PYY(22-36) N-α-Ac-A S L R H Y L N L V T R Q R Y-NH 2 (SEQ. ID No. 20) N-α-Ac- [Bth 27 ]PYY(22-36) N-α-Ac-A S L R H [Bth] L N L V T R Q R Y-NH, (SEQ. ID No. 21) N-α-Ac- [Bip 27 ]PYY(22-36> -α-Ac-A S L R H [Bip] L N L V T R Q R Y-NH 2 (SEQ. ID No. 22) N-α-Ac- [Nal 27 ]PYY(22-36> N-α-Ac-A S L R H [Nal] L N L V T R O R Y-NH ∑ (SEQ. ID No. 23) N-α-Ac- [Trp 27 ]PYY(22-36) N-α-Ac-A S L R H [Trp] L N L V T R O R Y-NH 2 (SEQ. ID No. 5) N-α-Ac- [Thi 27 ]PYY(22-36) N-α-Ac-A S L R H [Thi] L N L V T R Q R Y-NH 2 (SEQ. ID No. 6) N-α-Ac- [Tic 27 ] ]PPYYYY((2222--3366)) N-α-Ac-A S L R H [Tic] L N L V T R Q R Y-NHg (SEQ. ID No. 25) N-α-Ac- [Phe 27 ] PYY(25-36) N-α-Ac-H [Phe] L N L V T R Q R Y-NH-, (SEQ. ID No. 26) N-α-Ac- [Phe 27 ,Thi 36 )PYY(22-36) N-α-Ac-A S L R H [Phe] L N L V T R O R [Thi]-NH 2 (SEQ. ID No. 27) N-α-Ac- [Thz 26 ,Phe 27 ]PYY(22-36) N-α-Ac-A S L R [Thz] [Phe] L N L V T R Q R Y-NH 2 (SEQ. ID No. 28) N-α-Ac- [Pep 27 ] PYY(22-36) N-α-Ac-A S L R H [Pep] L N L V T R Q R Y-NH 2 (SEQ. ID No. 29) N-α-Ac- [Phe 2 ' 27 ]PYY(22-36) N-α-Ac- [Phe] S L R H [Phe] L N L V T R Q R Y-NH 2 (SEQ. ID No. 30) N-α-Ac- [Tyr 22 ,Phe 27 )PYY(22-36) N-α-Ac- [Tyr] S L R H [Phe] L N L V T R O R Y-NH 2 (SEQ. ID No. 7) N-α-Ac- [Trp 8 )PYY(22-36) N-α-Ac- A S L R H Y [Trp] N L V T R Q R Y-NH 2 (SEQ. ID No. 31) N-α-Ac- [Trp 30 ]PYY(22-36) N-α-Ac- A S L R H Y L N [Trp] V T R Q R Y-NH 2 (SEQ. ID No. 32) N-α-Ac-[Ala 6 ,Phe 27 ]PYY(22-36) N-α-Ac- A S L R [Ala] [Phe] L N L V T R Q R Y-NH 2 (SEQ. ID No. 33) N-α-Ac- [Bth 27 ]PYY(22-36) N-α-Ac- A S L R H [Bth] L N L V T R Q R Y-NH-, (SEQ. ID No. 34) N-α-Ac- [Phe 27 ]PYY(22-36) N-α-Ac- A S L R H [Phe] L N L V T R Q R Y-NH 2 (SEQ. ID No. 35) N-α-Ac- [Phe 27 ' 36 ]PYY(22-36) N-α-Ac- A S L R H [Phe] L N L V T R Q R [Phe]-NH 2 (SEQ. ID No. 36) N-α-Ac- [Phe 27 , D-Trp 32 ]PYY(22-36) N-α-Ac- A S L R H [Phe] L N L V [D-Trp] R Q R Y-NHj (SEQ. ID No. 37} ANALYSIS Binding Studies Preparation of 125 I-PYY labeled only at Tyr 36 and rat jejunal epithelial plasma membranes were performed according to standard methods (see, e.g., Laburthe et al. Endocrinology, supra; Servin et al. supra; Voisin et al. Ann. N. Y. Acad. Sci. 611:343, 1990). Binding experiments were conducted in a total volume of 0.25 ml 60 mM HEPES buffer, pH 7, containing 2% BSA, 0.1% bacitracin, 5 mM MgCl 2 and 0.05 nM 125 I-PYY with or without competing peptides. Bound and free peptides were separated by centrifugation at 20,000 X g for 10 min. Non-specific 125 I-PYY binding was determined in the presence of 1 μM unlabeled PYY represented 10% of the total binding. Short Circuit Current Measurements The antisecretory effects of the peptides were investigated by measuring the short-circuit current (SCC) in rat jejunal mucosa mounted in a Ussing chamber and automatically voltage clamped as described by Cox et al. (J. Physiol . supra) . Briefly, strips of mucosa were placed between two halves of perspex Ussing chambers (window size, 0.6 cm 2 ) containing oxygenated (95% 0 2 /5% . C0 2 ) Krebs-Henseleit solution (NaCl, 117 mM, KCl 4.7 mM, CaCl 2 , 2.5 mM; MgS0 4 1.2 mM, NaHC0 3 24.8 mM and glucose 11.1 mM) , pH 7.4, 37°C. Routinely, four preparations of jejunum were obtained from each animal and these exhibited comparable potential differences and SCC, but they were not paired. Preparations were automatically voltage clamped using a W-P dual voltage clamp and the SCC displayed continuously on pen recorders. Once a stable baseline SCC was reached, peptides were added to the basolateral reservoir only, and cumulative concentration-response profiles constructed. Data Analyses All points in the binding experiments are the mean of at least three experiments performed in duplicate. For clarity, the SEMs in the binding experiments are not shown in Fig. 2, but were less than 10%. Values of changes in SCC are quoted as μA/0.6cm 2 mean ± 1 SEM from between 3 and 7 different preparations. EC 50 values were calculated from pooled cumulative concentration - response curves using an iterative curve fitting program. Comparison of data groups (SCC recordings) were made using unpaired Student's t-tests where a p value <0.5 was considered statistically significant. There now follows the results of the biological activities of the compounds of the invention (see Table 1 and Table 2) . As described below, the tested compounds were assayed for purity and for their binding and antisecretory potencies in rat jejunum. Purified peptides were found to be > 96% homogeneous by analytical reversed phase chromatography and, in addition, had the expected amino acid composition and masses. For example. Fig. 1 shows the RP-HPLC chromatogram of N-α-Ac-[Phe 27 ]PYY(22-36) (SEQ. ID. NO. 3). The free peptides were further characterized by sequence analysis (see. Table 1 and Table 2) . The overall yields of the peptides were in the range of 10% to 30%. PYY, [im-DNP-His 26 ]PYY (SEQ. ID. NO. 9) and the analogs of PYY(22-36) (SEQ. ID. NO. 10) displaced 125 I-PYY bound to rat jejunal epithelial plasma membranes in a concentration-dependent manner. Although [im-DNP- His 26 ]PYY (SEQ. ID. NO. 9) and PYY(22-36) (SEQ. ID. NO. 10) were 20-times less potent than PYY based on IC 50 values, they displayed the same maximal response as the intact hormone (Fig. 2, Table 1). Substitution of Thr 32 with Ala as in [Ala 32 ]PYY(22-36) (SEQ. ID. NO. 11) resulted in the lowering of the binding potency while the replacement of both Ser 23 and Thr 32 with Ala further reduced the receptor affinity. Also, introduction of a negative charge at position 28 without altering the helicity as in [Glu 28 ]PYY(22-36) (SEQ. ID. NO. 13) decreased the binding possibly due to the disruption of the ionic interactions. Since the hydrophobic groups are known to increase the interaction with the receptors (Balasubramaniam et al. Biochem . Biophys . Res . Comm . 137:1041, 1986), the binding of a N-α-myristoyl- and N-α- naphthaleneacetyl-derivatives of PYY(22-36) was also determined. Both these analogs exhibited slightly lower binding affinity than PYY(22-36) (SEQ. ID. NO. 10) possibly due to increased steric hinderance. On the other hand, N-α-acetylation of PYY(22-36) (SEQ. ID. NO. 14) increased the receptor affinity four times. Further structure-activity studies with N-α-Ac-PYY(22-36) (SEQ. ID. NO. 20) revealed that substitution of Tyr 36 with N-Me- Tyr or His 26 with p.Cl-Phe lowers the binding potency. However, replacement of Tyr 27 with Phe increased the receptor affinity by 28%. As a control, the binding of PYY(22-36) (SEQ. ID. NO. 10) and several of its analogs were also tested. However, none of these analogs inhibited the binding of 125 I-PYY even at 10 μM. In mucosal preparations of rat jejunum PYY(22-36). (SEQ. ID. NO. 10) analogs reduced the baseline SCC in a concentration dependent manner (Fig. 3A and B) and calculated EC 50 values are listed in Table 1. The PYY(22- 36) (SEQ. ID. NO. 10) analogs were generally less potent as antisecretory agents than as inhibitors of binding. The order of analog potency was similar to that from binding studies with two notable exceptions, namely N-α- myristoyl-PYY(22-36) (SEQ. ID. NO. 18) and N-α- naphthaleneacetyl-PYY(22-36) (SEQ. ID. NO. 19). N-α- acetylation and substitution of Tyr 27 with Phe increased the antisecretory potency of PYY(22-36) and this analog, N-α-Ac-[Phe 27 ] PYY(22-36) (SEQ. ID. NO. 3), was only 9- times less potent than the intact hormone. Furthermore, there was no significant difference between the maximal inhibitory responses, these being - 12.6±2.4 and - 12.0±1.3μ A/0.6cm 2 for PYY (440 nM, n = 6) (SEQ. ID. NO. 1) and N-α-Ac-[Phe 27 ] PYY(22-36) (1.4 μM, n = 7) (SEQ. ID. O. 3) , respectively. TABLE 1: Comparison of the binding and antisecretory potencies of PYY, PYY fragments and their analogs PEPTIDES MH+ (Calc.) BINDING 13 SCC b (min) IC u ς 5 n 0(nM) ECc 5 n 0(nM) a: isocratic, 27X CH,CN containing 0.1X TFA; b: mean of three separate experiments; c: isocratic, 32X CH-.CN containing 0.1X TFA; d: from reference 10; n.d.: not determined N-α-myristoyl-PYY(22-36) (SEQ. ID. NO. 18) and N-α- naphthaleneacetyl-PYY(22-36) (SEQ. ID. NO. 19) analogs, in contrast to their moderate binding potency, exhibited poor antisecretory responses with threshold concentrations of about 20nM and EC 50 values greater than 2 and 30 μM respectively. After a cumulative concentration of 7.4 μM, N-α-myristoyl-PYY(22-36) (SEQ. ID. NO. 18) reduced the basal SCC by - 5.2±0.6μA/0.6cm 2 (n = 7) . Subsequent addition of PYY (100 nM) further reduced the SCC by -10.2±0.7μA/0.6cm 2 (n = 7) and this was not significantly different from control responses to PYY(22-36) (SEQ. ID. NO. 10) could antagonize PYY responses, three tissues were treated with the analog (lμM) and PYY concentration- response curves were constructed and compared with controls. The fragment reduced the basal current by - 0.4±0.3 μA/0.6cm 2 and the resultant PYY EC 50 value (4.411.2 nM, n = 3) did not differ significantly from that of the nontreated controls (2.611.1 nM, n = 3) . These results show that modification of the active site of PYY (SEQ. ID. NO. 1), PYY(22-36) (SEQ. ID. NO. 10) , can lead to a substantial increase in both the binding and antisecretory potencies of this fragment. The key analogs in this series exhibited the following order of potency: PYY (SEQ. ID. NO. 1) > N-α-Ac- [Phe 27 ]PYY(22-36) (SEQ. ID. NO. 3) > N-α-Ac-PYY(22-36) (SEQ. ID. NO. 14) > PYY(22-36) (SEQ. ID. NO. 10). Furthermore, our investigations revealed that the hydroxyl groups of Ser 23 and Thr 32 as well as the imidazole group of His 26 are important for interaction with intestinal PYY- preferring receptors. Although there was, in general, a good correlation between the binding and antisecretory potencies of the analogs, there were also notable exceptions. N-α-myristoyl-PYY(22-36) (SEQ. ID. NO. 18) and -α- naphthaleneacetyl-PYY(22-36) (SEQ. ID. NO. 19) analogs inhibited 125 I-PYY binding with moderate potency, but exhibited poor antisecretory responses. This observation suggested that these analogs may be antagonists. However, prior pretreatment of jejunal membranes with these analogs failed to significantly alter the antisecretory responses to PYY and the reason for the discrepancy remains unclear at present. Table 2 and Fig. 4 present the IC 50 values for additonal PYY(22-36) (SEQ. ID. NO. 10) and PYY (25-36) analogs. Based on the results presented in Table 2 the analogs in this series exhibited the following order of potency: N-α-Ac-[Tic 27 ]PYY(22-36) (SEQ. ID. NO. 25) < N-α-Ac- [Bip 27 ]PYY(22-36) (SEQ. ID. NO. 22) < N-α-Ac- [Nal 27 ]PYY(22-36) (SEQ. ID. NO. 23) < N-α-Ac- [Bth 27 ]PYY(22-36) (SEQ. ID. NO. 21) < N-α-Ac- [Phe 27 ]PYY(22-36) (SEQ. ID. NO. 3) < N-α-Ac-[Phe 27 ]PYY(25- 36) (SEQ. ID. NO. 26) < N-α-Ac-[Trp 27 ]PYY(22-36) (SEQ. ID. NO. 5) < N-α-Ac-[Thi 27 ]PYY(22-36) (SEQ. ID. NO. 6) < N-α- AC-PYY(22-36) (SEQ. ID. NO. 14) < PYY (SEQ. ID. NO. 1). TABLE 2 Comparison of Receptor Binding Data for PYY and PYY analogs NPY/PYY receptors characterized to date have been broadly classified into Y-l, Y-2 and Y-3 subtypes (Balsubramaniam et al. J. Biol . Chem. 265:14724, 1990; Michel, Trends Pharmacol . Sci . 12:389, 1991). Both Y-l and Y-2 receptors exhibit a preference for PYY over NPY, and more significantly C-terminal fragments of NPY and PYY are effective only at the Y-2 subtype. Y-3 receptors, on the other hand, exhibit a greater affinity for NPY than PYY. Since rat jejunal mucosa antisecretory responses show an order of agonist potency PYY (SEQ. ID. NO. 1)> NPY (SEQ. ID. NO. 24) > PYY(13-36) (SEQ. ID. NO. 32) > NPY(13-36) (SEQ. ID. NO. 33) these epithelial receptors are Y-2 like, and are completely insensitive to the Y-l selective agonist [Pro 34 ]NPY (Cox et al. Peptides, supra) . The results further describe N-α-Ac-PYY(22-36) (SEQ. ID. NO. 14) and N-α-Ac-[Phe 27 ]PYY(22-36) (SEQ. ID. NO. 3) to be more potent than PYY(22-36) (SEQ. ID. NO. 10) and the corresponding C-ter inal fragments of NPY of varying lengths (Cox et al. Br. J. Pharmacol , supra) . The higher affinity for PYY (SEQ. ID. NO. 1) and its C- terminal fragments compared with NPY (SEQ. ID. NO. 24) and its respective fragments is in agreement with the order of potency obtained from receptor binding studies with rat intestinal epithelial membranes (Laburthe et al. supra ; Laburthe, supra ; Voisin et al. Ann . N. Y. Acad. Sci . supra ; Voisin et al. Am . J. Physiol . ) In addition, analogs listed in Table 3 were synthesized as described above and tested for binding activity. The results shown in Table 3 demonstrate that N-α-Ac-[Tyr 22 , Phe 27 ]PYY(22-36) (SEQ. ID. NO. 7) is similar in its competitive binding as PYY (SEQ. ID. NO. 1) , indicating that the introduction of an aromatic amino acid, e.g., Tyr, at position 22 is an effective PYY analog. TABLE 3 USE In the practice of the method of the present invention, an effective amount of an any one or combination of the analogs of the invention, e.g., N-α- Ac-[Phe 27 ]PYY(22-36) (SEQ. ID. NO. 3), N-α-Ac- [Trp 27 ]PYY(22-36) (SEQ. ID. NO. 24), N-α-Ac-[Phe 27 ]PYY(25- 36) (SEQ. ID. NO. 3), N-α-Ac-[Thi 27 ]PYY(22-36) (SEQ. ID. NO. 6) or derivative thereof, is administered via any of the usual and acceptable methods known in the art, either singly or in combination with another compound or compounds of the present invention. These compounds or compositions can thus be administered orally (e.g., buccal cavity), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously) , rectally ( e.g., by. suppositories or washings), transdermally (e.g., skin electroporation) or by inhalation (e.g., by aerosol), and in the form or either solid, liquid or gaseous dosage, including tablets and suspensions. The administration can be conducted in a single unit dosage form with continuous therapy or in a single dose therapy ad libitum. Thus, the method of the present invention is practiced when relief of symptoms is specifically required or perhaps imminent. Alternatively, the method of the present invention is effectively practiced as continuous or prophylactic treatment. Useful pharmaceutical carriers for the preparation of the compositions hereof, can be solids, liquids or gases; thus, the compositions can take the form of tablets, pills, capsules, suppositories, powders, enterically coated or other protected formulations (e.g. binding on ion-exchange resins or packaging in lipid- protein vesicles) , sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like. The carrier can be selected from the various oils including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly (when isotonic with the blood) for injectable solutions. For example, formulation for intravenous administration comprise sterile aqueous solutions of the active ingredient(s) which are prepared by dissolving solid active ingredient(s) in water to produce an aqueous solution, and rendering the solution sterile. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The compositions may be subjected to conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers and the like. Suitable pharmaceutical carriers and their formulation are described in Remington 's Pharmaceutical Sciences by E.W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable carrier so as to prepare the proper dosage form for proper administration to the recipient. The dose of the compound of the present invention for treating the above-mentioned disorders varies depending upon the manner of administration, the age and the body weight of the subject, and the condition of the subject to be treated, and ultimately will be decided by the attending physician or veterinarian. Such amount of the active compound as determined by the attending physician or veterinarian is referred to herein as a "therapeutically effective amount". Thus, a typical administration is oral administration or parenteral administration. The daily dose in the case of oral administration is typically in the range of 0.1 to 100 mg/kg body weight, and the daily dose in the case of parenteral administration is typically in the range of 0.001 to 50 mg/kg body weight. To be effective for the prevention or treatment of gastroenterological disorders, especially infectious (e.g. viral or bacterial) or inflammatory diarrhea, or diarrhea resulting from surgery, it is important that the therapeutic agents be relatively non-toxic, non-antigenic and non-irritating at the levels in actual use. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.

Claims: Claims : 1. A compound having the formula: Ri R 3 \ / R 2 -χ- A 22_ A 23. A 24. A 25_ A 26. A 27_ A 28_ A 29_ A 30. A 31_ A 32_ y _ R4 wherein X is a chain of 0-5 amino acids, inclusive, the N-terminal one of which is bonded to R x and R 2 ; Y is a chain of 0-4 amino acids, inclusive, the C-terminal one of which is bonded to R 3 and R 4 ; R λ is H, C 1 -C 12 alkyl, C 6 -C 18 aryl, C^C*-^ acyl, C 7 -C 18 aralkyl, or C 7 -C 18 alkaryl; R 2 is H, C.-.-C--^ alkyl, C 6 -C 18 aryl, C^C-*^ acyl, C 7 -C 18 aralkyl, or C 7 -C 18 alkaryl; A 22 is an aromatic amino acid, Ala, Aib, Anb, N-Me-Ala, or is deleted; A 23 is Ser, Thr, Ala, Aib, N-Me-Ser, N-Me-Thr, N- Me-Ala, D-Trp, or is deleted; A 24 is Leu, Gly, lie, Val, Trp, Aib, Anb, N-Me-Leu, or is deleted; A 25 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- €-NH-R (where R is H, a branched or straight hain C 1 -C 10 alkyl group, or an aryl group) , Orn or is deleted; A 25 is Ala, His, Thr, 3-Me-His, 1-Me-His, ,9-pyrozolylalanine, N-Me-His, Arg, Lys, homo- Arg, diethyl-homo-Arg, Lys-e-NH-R (where R is H, a branched chain or straight chain alkyl group, or an aryl group), Orn,or is deleted; A 27 is an aromatic amino acid other than Tyr; A 28 is Leu, lie, Val, Trp, Aib, Anb, or N-Me-Leu; A 29 is Asn, Ala, Gin, Gly, Trp, or N-Me-Asn; A 30 is Leu, lie, Val, Trp, Aib, Anb, or N-Me-Leu; A 31 is Val, He, Trp, Aib, Anb, or N-Me-Val; A 32 is Thr, Ser, N-Me-Ser, N-Me-Thr, or D-Trp; R 3 is H, C-t-C-^ alkyl, C 6 -C 18 aryl, ^-c^ acyl, C 7 -C 18 aralkyl, or C 7 -C 18 alkaryl; and R 4 is H, C 1 -C 12 alkyl, C 6 -C 18 aryl, C 1 -C 12 acyl, C 7 -C 18 aralkyl, C 7 -C 18 alkaryl, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein A 27 is Phe, Nal, Bip, Pep, Tic, Trp, Trp, Bth, Thi, or Dip. 3. The compound of claim 1, where X is A 17 -A 18 - A i9_ A 20_ A 2i W herein A 17 is Cys, Leu, He, Val, Aib, Anb, or N-Me-Leu; A 18 is Cys, Ser, Thr, N-Me-Ser, or N-Me-Thr; A 19 is Cys, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or C 6 -C 18 aryl group) , or Orn; A 20 is an aromatic amino acid or Cys; and A 21 is an aromatic amino acid, Cys, or a pharmaceutically acceptable salt thereof. 4. The compound of claim 1, where Y is A 33 - A 34_ A 35_ A 36 where i n A 33 is Cys, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or C 6 -C 18 aryl group) , or Orn; A 34 is Cys, Gin, Asn, Ala, Gly, N-Me-Gln, Aib, or Anb; A 35 is Cys, Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C^C-^ alkyl group, or C 6 -C 18 aryl group) , or Orn; and A 36 is an aromatic amino acid, Cys, or a pharmaceutically acceptable salt thereof. 5. The compound of claim 4, wherein said compound has the formula: N-α-Ac-Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg- Gln-Arg-Tyr-NH 2 (SEQ. ID. NO. 3), or a pharmaceutically acceptable salt thereof. 6. The compound of claim 4, wherein said compound has the formula: H-Ala-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln- Arg-Tyr-NH 2 (SEQ. ID. NO. 4) , or a pharmaceutically acceptable salt thereof. 7. The compound of claim 4, wherein said compound has the formula: N-α-Ac-Ala-Ser-Leu-Arg-His-Trp-Leu-Asn-Leu-Val-Thr-Arg- Gln-Arg-Tyr-NH 2 (SEQ. ID. NO. 5) , or a pharmaceutically acceptable salt thereof. 8. The compound of claim 4, wherein said compound has the formula: N-α-Ac-Ala-Ser-Leu-Arg-His-Thi-Leu-Asn-Leu-Val-Thr-Arg- Gln-Arg-Tyr-NH 2 (SEQ. ID. NO. 6) , or a pharmaceutically acceptable salt thereof. 9. The compound of claim 4, wherein said compound has the formula: N-α-Ac-Tyr-Ser-Leu-Arg-His-Phe-Leu-Asn-Leu-Val- Thr-Arg-Gln-Arg-Tyr-NH 2 (SEQ. ID. NO. 7), or a pharmaceutically acceptable salt thereof. 10. A compound having the formula: *ι R 3 \ / R 2 -A 25 -A 26 -A 27 -A 28 -A 29 -A 30 -A 31 -A 32 -Y-R 4 wherein the N-terminal amino acid is bonded to R 1 and R 2 ; Y is a chain of 0-4 amino acids, inclusive the C-terminal one of which is bonded to R 3 and R 4 ; R- L is H, C 2 -C 12 alkyl, C 6 -C 18 aryl, C^C-^ acyl, c 7 ~ i 8 aralkyl, or C 7 -C 18 alkaryl; R 2 is H, C 1 -C 12 alkyl, C 6 -C 18 aryl, C j -C-^ acyl, C 7 -C 18 aralkyl, or C 7 -C 18 alkaryl; A 25 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e-NH-R (where R is H, a branched or straight chain C^C-^ alkyl group, or an aryl group) , Orn or is deleted; A 26 is Ala, His, Thr, 3-Me-His, 1-Me-His, ,9-pyrozolylalanine, N-Me-His, Arg, Lys, homo- Arg, diethyl-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain ^-c^ alkyl group, or an aryl group) , Orn or is deleted; A 27 is an aromatic amino acid; A 28 is Leu, He, Val, Trp, Aib, Anb, or N-Me-Leu; A 29 is Asn, Ala, Gin, Gly, Trp, or N-Me-Asn; A 30 is Leu, He, Val, Trp, Aib, Anb, or N-Me-Leu; A 31 is Val, He, Trp, Aib, Anb, or N-Me-Val; A 32 is Thr, Ser, N-Me-Ser, N-Me-Thr, or D-Trp; R 3 is H, C j^ -C^ alkyl, C 6 -C 18 aryl, C.-.-C j ^ acyl, C 7 -C 18 aralkyl, or C 7 -C 18 alkaryl; and R 4 is H, acyl, C 7 -C 18 aralkyl or C 7 -C 18 alkaryl, or a pharmaceutically acceptable salt thereof. 11. The compound of claim 10, wherein A 27 is Phe, Nal, Bip, Pep, Tic, Trp, Bth, Thi, or Dip. 12. The compound of claim 10, wherein Y is A 33 -. A 34_ A 35_ A 36 where i n A 33 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e-NH-R (where R is H, a branched or straight chain C^C-*^ alkyl group, or C 6 -C 18 aryl group) , Cys, or Orn; A 34 is Cys, Gin, Asn, Ala, Gly, N-Me-Gln, Alb, or Anb; A 35 is Arg, Lys, homo-Arg, diethyl-homo-Arg, Lys- e-NH-R (where R is H, a branched or straight chain C^C-*^ alkyl group, or C 6 -C 18 aryl group) , Cys, or Orn; and A 36 is an aromatic amino acid, Cys, or a pharmaceutically acceptable salt thereof. 13. The compound of claim 12, wherein said compound has the formula: N-α-Ac-Arg-His-Phe-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr- NH 2 (SEQ. ID. NO. 26) , or a pharmaceutically acceptable salt thereof. 14. A therapeutic composition capable of decreasing excess intestinal water and electrolyte secretion, said composition comprising a therapeutically effective amount of the compound of claim 1 and claim 10, together with a pharmaceutically acceptable carrier substance. 15. A method of decreasing excess intestinal water and electrolyte secretion in a mammal, said method comprising administering to said mammal a therapeutically effective amount of the composition of claim 14. 16. A method of regulating cell proliferation in a mammal, said method comprising administering to said mammal a therapeutically effective amount of the composition of claim 14. 17. A method of augmenting nutrient transport in a mammal, said method comprising administering to said mammal a therapeutically effective amount of the composition of claim 14. 18. A method or regulating lipolysis in a mammal, said method comprising adminsitering to said mammal a therapeutically effective amount of the composition of claim 14. 19. A method of regulating blood flow in a mammal, said method comprising adminsitering to said mammal a therapeutically effective amount of the composition of claim 14. 20. A di eric compound comprising either two peptides of claim 10, or one peptide of claim l or one peptide of claim 10, wherein said dimer is formed by either an amide bo, or a disulfide bridge between said two peptides.

Inventors: BALASUBRAMANIAM AMBIKAIPAKAN, BALASUBRAMANIAM, AMBIKAIPAKAN
Applicants: UNIV CINCINNATI, UNIVERSITY OF CINCINNATI
Application year: 1994
Main classification: A61K37
IPC codes: A61K38, A61P1, A61P3, C07K7, C07K14